Lorentz-Shaped Comet Dust Trail Cross Section from New Hybrid Visual and Video Meteor Counting Technique - Implications for Future Leonid Storm Encounters

A new hybrid technique of visual and video meteor observations was developed to provide high precision near real-time flux measurements for satellite operators from airborne platforms. A total of 33,000 Leonids. recorded on video during the 1999 Leonid storm, were watched by a team of visual observers using a video head display and an automatic counting tool. The counts reveal that the activity profile of the Leonid storm is a Lorentz profile. By assuming a radial profile for the dust trail that is also a Lorentzian, we make predictions for future encounters. If that assumption is correct, we passed 0.0003 AU deeper into the 1899 trailet than expected during the storm of 1999 and future encounters with the 1866 trailet will be less intense than. predicted elsewhere

Macrocephaly and developmental delay caused by missense variants in RAB5C

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway

A Delphi Survey Study to Formulate Statements on the Treatability of Inherited Metabolic Disorders to Decide on Eligibility for Newborn Screening

The Wilson and Jungner (W&amp;J) and Andermann criteria are meant to help select diseases eligible for population-based screening. With the introduction of next-generation sequencing (NGS) methods for newborn screening (NBS), more inherited metabolic diseases (IMDs) can technically be included, and a revision of the criteria was attempted. This study aimed to formulate statements and investigate whether those statements could elaborate on the criterion of treatability for IMDs to decide on eligibility for NBS. An online Delphi study was started among a panel of Dutch IMD experts (EPs). EPs evaluated, amended, and approved statements on treatability that were subsequently applied to 10 IMDs. After two rounds of Delphi, consensus was reached on 10 statements. Application of these statements selected 5 out of 10 IMDs proposed for this study as eligible for NBS, including 3 IMDs in the current Dutch NBS. The statement: ‘The expected benefit/burden ratio of early treatment is positive and results in a significant health outcome’ contributed most to decision-making. Our Delphi study resulted in 10 statements that can help to decide on eligibility for inclusion in NBS based on treatability, also showing that other criteria could be handled in a comparable way. Validation of the statements is required before these can be applied as guidance to authorities.</p

Genetic defect of the sodium-dependent multivitamin transporter : A treatable disease, mimicking biotinidase deficiency

The sodium-dependent multivitamin transporter that facilitates the uptake of the water-soluble vitamins biotin, pantothenic acid, and the vitamin-like substance lipoate is coded by the SLC5A6 gene. Variants in this gene cause a relatively novel treatable metabolic disorder. Here we describe the second case. A 17-month-old girl presented with hypoglycemia (2.0 mmol/L) and severe metabolic acidosis (pH 6.87), leading to resuscitation. Her history revealed feeding problems from birth and poor weight gain. Metabolic investigation showed elevated plasma C3-carnitine and C5-OH-carnitine. Urine analysis showed persistently elevated excretion of 3-OH-isovaleric acid. Biochemically, the combination of elevated C5-OH-carnitine and increased excretion of 3-OH-isovaleric acid seemed compatible with biotinidase deficiency. Supplementation with biotin was started. Biotinidase activity in plasma showed only marginally decreased activity, which was considered insufficient explanation for her clinical symptoms. Subsequent trio-based whole exome sequencing revealed compound heterozygosity for variants in the SLC5A6 gene. Upon increasing the dosage of biotin supplementation and introduction of pantothenic acid supplementation, a striking clinical improvement was seen

Differentiation between chronic rejection and chronic cyclosporine toxicity by analysis of renal cortical mRNA

Differentiation between chronic rejection and chronic cyclosporine toxicity by analysis of renal cortical mRNA.BackgroundIn kidney transplantation, chronic allograft nephropathy (CAN) is the major cause of graft loss. Causes of CAN include chronic rejection and chronic cyclosporine A (CsA) nephrotoxicity. It is necessary to differentiate between these two entities in order to apply the appropriate therapeutic regimen for the individual patient, but this is hampered by the lack of discriminating functional and morphologic parameters. We investigated whether renal cortical mRNA levels for several matrix proteins can serve as discriminating parameters.MethodsPatients with chronic rejection (N = 19) and chronic CsA toxicity (N = 17) were selected by clinical and histologic criteria. Protocol biopsies without histologic abnormalities, taken at 6 months after transplantation from patients receiving CsA, were used as controls (N = 6). Total RNA was extracted from the renal biopsy tissue, and mRNA levels of transforming growth factor-β (TGF-β) and the extracellular matrix (ECM) molecules collagen Iα1, IIIα1, IVα3, decorin, fibronectin, and laminin β2 were measured by real-time polymerase chain reaction (PCR).ResultsIn both patient groups, the mean collagen IVα3 and fibronectin mRNA levels were significantly elevated compared to those in controls, whereas only in CsA toxicity were the laminin β2 and TGF-β mRNA levels significantly increased. The increase of laminin β2 and TGF-β mRNA levels was significantly higher in the CsA toxicity group than in the chronic rejection group (P < 0.001 and P = 0.004, respectively). Receiver-operating characteristic (ROC) curve analysis showed that with a 15.6-fold increase in laminin β2 mRNA expression as cut-off point, the presence of CsA toxicity could be predicted with an 87% sensitivity and an 88% specificity.ConclusionRenal laminin β2 and TGF-β mRNA levels can be used to differentiate between chronic rejection and chronic CsA toxicity in renal transplants. The method of mRNA quantification might be applicable as an additional diagnostic tool in clinical practice

A False-Negative Newborn Screen for Tyrosinemia Type 1-Need for Re-Evaluation of Newborn Screening with Succinylacetone

Undiagnosed and untreated tyrosinemia type 1 (TT1) individuals carry a significant risk for developing liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Elevated succinylacetone (SA) is pathognomonic for TT1 and therefore often used as marker for TT1 newborn screening (NBS). While SA was long considered to be elevated in every TT1 patient, here we present a recent false-negative SA TT1 screen. A nine-year-old boy presented with HCC in a cirrhotic liver. Additional tests for the underlying cause unexpectedly revealed TT1. Nine years prior, the patient was screened for TT1 via SA NBS with a negative result: SA 1.08 µmol/L, NBS cut-off 1.20 µmol/L. To our knowledge, this report is the first to describe a false-negative result from the TT1 NBS using SA. False-negative TT1 NBS results may be caused by milder TT1 variants with lower SA excretion. Such patients are more likely to be missed in NBS programs and can be asymptomatic for years. Based on our case, we advise TT1 to be considered in patients with otherwise unexplained liver pathology, including fibrosis, cirrhosis and HCC, despite a previous negative TT1 NBS status. Moreover, because the NBS SA concentration of this patient fell below the Dutch cut-off value (1.20 µmol/L at that time), as well as below the range of cut-off values used in other countries (1.29-10 µmol/L), it is likely that false-negative screening results for TT1 may also be occurring internationally. This underscores the need to re-evaluate TT1 SA NBS programs.</p

C4d Staining In Renal Allograft Biopsies with Early Acute Rejection and Subsequent Clinical Outcome

Nephrolog

Biochemical studies in fibroblasts to interpret variants of unknown significance in the abcd1 gene

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected